A longitudinal multimodal in vivo molecular imaging study of the 3xTg-AD mouse model shows progressive early hippocampal and taurine loss

Abstract

The understanding of the natural history of Alzheimer’s disease (AD) and temporal trajectories of in vivo molecular mechanisms requires longitudinal approaches. A behavioral and multimodal imaging study was performed at 4/8/12 and 16 months of age in a triple transgenic mouse model of AD (3xTg-AD). Behavioral assessment included the open field and novel object recognition tests. Molecular characterization evaluated hippocampal levels of amyloid (A ) and hyperphosphorylated tau. Magnetic resonance imaging (MRI) included assessment of hippocampal structural integrity, blood–brain barrier (BBB) permeability and neurospectroscopy to determine levels of the endogenous neuroprotector taurine. Longitudinal brain amyloid accumulation was assessed using 11 C Pittsburgh compound B positron emission tomography (PET), and neuroinflammation/microglia activation was investigated using 11 C-PK1195. We found altered locomotor activity at months 4/8 and 16 months and recognition memory impairment at all time points. Substantial early reduction of hippocampal volume started at month 4 and progressed over 8/12 and 16 months. Hippocampal taurine levels were significantly decreased in the hippocampus at months 4/8 and 16. No differences were found for amyloid and neuroinflammation with PET, and BBB was disrupted only at month 16. In summary, 3xTg-AD mice showed exploratory and recognition memory impairments, early hippocampal structural loss, increased A and hyperphosphorylated tau and decreased levels of taurine. In sum, the 3xTg-AD animal model mimics pathological and neurobehavioral features of AD, with early-onset recognition memory loss and MRI-documented hippocampal damage. The early-onset profile suggests temporal windows and opportunities for therapeutic intervention, targeting endogenous neuroprotectors such as taurine.

Progression of Alzheimer's disease and effect of scFv‐h3D6 immunotherapy in the 3xTg‐AD mouse model: An in vivo longitudinal study using Magnetic Resonance Imaging and Spectroscopy

“…Whole brain and ventricle atrophy has been previously reported in 15‐mo 3xTg‐AD mice while other studies at the same age could not detect brain volume differences . Recent studies, using voxel based morphometry, have described reduced hippocampal volume at 4‐mo in accordance with our findings. In this study, we have also been able to detect early volumetric abnormalities in all the regions analyzed (cortex, cerebellum, cerebrum, and the whole brain).…”

“…The triple transgenic mouse model (3xTg‐AD) is extensively used in AD research and reproduces both amyloid and tau pathologies in a regional and temporal pattern analogous to AD patients, which makes it very valuable for longitudinal studies . In vivo magnetic resonance imaging (MRI) and proton spectroscopy ( 1 H‐MRS) have recently begun to be used for the characterization of the triple transgenic Alzheimer's Disease mouse model . MRI not only provides structural information but also relevant functional evidence when acquiring multiparametric MRI maps.…”

“…In this study, different MRI/MRS parameters were analyzed at 5, 7, 9, and 12‐mo. MRI was used to determine the volume of different cerebral regions involved in the disease, as a reduction in cerebral volume is associated with atrophy and neurodegeneration due to neuron loss in humans and mice . We have also quantified the T 2 value, whose changes are associated with the appearance of amyloid plaques, neuroinflammation, and neurodegeneration .…”

WITHDRAWN: Do the retina and brain share similar molecular and cellular pathological footprints? Insights from an Alzheimer´s disease animal model

“…We recently reported the existence of structural and functional changes in the brain and retina of 3xTg-AD mice (15,16). These alterations occur as early as 4 months of age.…”

“…We recently described structural and functional changes in the brain and retina of the triple transgenic mouse model of AD (3xTg-AD) (15,16), a well characterized model that develops both senile plaques and neurofibrillary tangles in a progressive and age-dependent manner (17). We reported that 3xTg-AD mice, as early as 4 and 8 months of age, already present impaired locomotion activity and recognition memory as well as a decrease of hippocampal volume and taurine levels (15).…”